The introduction of HTS methods (High Throughput Screening) in early drug discovery together with an enhanced demand on selectivity have in recent years increased the number of candidate drugs with a low aqueous solubility. In order to minimise administration volumes and obtain a high bioavailability it is of great practical importance for pharmaceutical formulators to have the ability to increase the solubility of these compounds when suitable dosage forms are developed. These preparations can be intended both for assessment of medical effect in humans and safety studies in animals during the development of a new drug, and as the final pharmaceutical dosage form for the marketed product.
One commonly used method to increase the solubility of poorly soluble compounds is to solubilize the compound in a micellar system by the use of surfactants. [“The Theory and Practice of Industrial Pharmacy” 2nd ed. Lea & Febiger, 1976, p. 108-111.]
The main advantages with micellar systems are the stability over a wide composition range, simplicity of preparation, low viscosity and the fact that a micellar system is a thermodynamically stable single phase which is optically clear. Surfactants can be divided into anionic, e.g. sodium lauryl sulfate, cationic, e.g. cetyl trimethyl-ammonium bromide, zwitter-ionic, e.g. alkyl betaines and non-ionic surfactants, e.g. ethoxylated sorbitanoleate, according to their chemical properties.
The choice of surfactants for use in pharmaceutical applications depends to some extent on the route of adminstration and is rather limited since most surface-active compounds are not tolerated well enough for pharmaceutical use. For parenteral use ionic surfactants are not suitable since these cause hemolysis of red blood cells and destruction of T lymphocyte cells at low concentrations. [“Solubility & Solubilization in aqueous media.”, Yalkowsky, 1999]. The most accepted surfactants for parenteral use are phospholipids and non-ionic surfactants. For oral use non-ionic surfactants are usually preferred but ionic-surfactants have been used in low concentrations.
Non-ionic surfactants used in pharmaceutical applications today include substances/mixtures such as ethoxylated castor oil (Cremophor EL), ethoxylated sorbitan fatty acid esters, e.g. polyoxyethylene sorbitan monooleate (Tween 80), sorbitan fatty acid esters, e.g. sorbitan monooleate (Span 80), ethoxylated hydroxystearic acid, e.g. polyethylene glycol 660 (12-)hydroxystearate (Solutol HS15), etylene and propylene oxide block copolymers (Pluronic F68) and fatty acid esters of glycerol (Imwitor 742).
The above described non-ionic surfactants which are presently used in pharmaceutical applications do, however, exhibit a number of disadvantages.
For example, the commercial non-ionic surfactants available for pharmaceutical formulators are complex mixtures of different molecules which makes the characterisation of these products very difficult, giving an expensive and tedious analytical process to ensure adequate quality (for i.a. pharmaceutical applications).
Recent studies on adverse effects on epithelial cells have shown that commercial non-ionic surfactants have a profound effect on epithelial cells in concentrations typically used for solubilisation (Östh, Karin, Thesis: The horizontal Ussing chamber method in studies of nasal drug delivery, 2002. Faculty of Pharmacy, Uppsala University).
It is also well known that surface-active compounds often cause hemolysis at low concentrations when administered parenterally.
The existing non-ionic surfactants systems used for parenteral administration are all based on polyethylene glycol derivatives. Although there are several pharmaceutical products for parenteral administration on the market containing these surfactants, they all suffer from quite severe side effects, like release of histamine which in severe cases can lead to anaphylactic chocks (Lorentz et al., Agents and Actions, Vol. 12, 1/2, 1982).
Histamine release is believed to be caused by impurities in the commercial products and since the non-ionic surfactants used are very complex mixtures of different molecules it is not possible to purify existing products. Also in such situations it is hard to relate any side-effects to a particular molecule. (Vulfsson. In “Novel Surfactants”. Holmberg editor. Marcel Dekker 1988. p. 279-97.)
In EP 0017059 A1, reaction products of monohydroxy fatty acids with ethylene oxide in a given molar ratio are mentioned (the Solutol® type of compounds).
The products formed are mixtures of monoesters or diesters of polyetylene glycol (PEG) and monohydroxy fatty acids or estolides, the latter commonly known as a generic name for linear oligomeric polyesters of hydroxyl fatty acids wherein the carboxyl group and hydroxyl group of hydroxyl fatty acids are dehydrated to form oligomers. The products of EP 0017059A1 comprising two or more monohydroxy fatty acids where the monohydroxy fatty acid of the estolide may either be attached directly to the hydroxyl group of another fatty acid or to a hydroxyl group of a PEG chain attached to the aforementioned hydroxyl group of a monohydroxy fatty acid. These reaction products are stated to be used especially as dissolution enhancers for pharmaceutical purpose. With these kind of compounds, the resulting synthesis product will always be a mixture of compounds. Solutol HS 15 is such a product. Short PEG chains (one type of polyoxyalkylene glycol, or POAG, chain) are a characteristic feature of the compounds claimed in EP 0017059 A1.
U.S. Pat. No. 6,365,637 claims the use of esters or amides of hydroxylated carboxylic acids as solubilizers, for i.a. pharmaceutical purposes. These compounds all have short PEG chains. Furthermore, the optional use of a dimerized fatty acid, as described in U.S. Pat. No. 6,365,637, of commercial quality including both monomeric, dimeric, trimeric and higher polymerized acids in the synthesis is a draw-back when one desires to obtain highly pure compounds.